Note: Descriptions are shown in the official language in which they were submitted.
l~G3~:~5
- 1-
The invention relates to a novel cyclic compound,
namely 5-(indol-3-ylmethylene)-1,3,-dimethyl-2-methylimino-4-
imidazolidinone and to a process for the manufacture
thereof.
The compound can exist in isomeric forms, e.g. the
: E-isomer of the formula
H
U - CH3
CH3
and the Z-isomer of the formula
/ ~ \ CE Z-l
N - CH3
G3~35
The compound of formula E-l,
i.e. (E)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-
imidazolidinone, exists in low quantities in, and can
be isolated by extraction from, a sponge belonging to the
order Dictyoceratida, which can be collected on the
Australian seacoasts. The substantially pure (E)-5-(indol-3-
ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone,
i.e. said compound free from the other compounds contained
in the sponge, thus constitutes a further feature of the
present invention. 5-(Indol-3-ylmethylene)-1,3-dimethyl-2-
- methylimino-4-imidazolidinone can be prepared in accordance
with the invention by a process characterized in that
a) indole-3-aldehyde is condensed with 1,3-dimethyl-2-
methylimino-4-imidazolidinone, or
b) 5-(indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-imidazo-
lidinone is reacted with a methylating agent.
In another aspect the invention provides a process
for the preparation of (E)-5-(indol-3-ylmethylene)-1,3-
dimethyl-2-methylimino-4-imidazolidinone characterized in that
a) indole-3-aldehyde is condensed with 1,3-dimethyl-2-
methylimino-4-imidazolidinone, and the E-product is separated
from the resulting E-Z mixture; or
b) (E)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-
imidazolidinone is reacted with a methylating agent.
-- 2 --
,3~
In yet another aspect the invention provides a
process for the preparation of (Z)-5-(indol-3-ylmethylene)-
; 1,3-dimethyl-2-methylimino-4-imidazolidinone characterized
in that
a) indole-3-aldehyde is condensed with 1,3-dimethyl-2-
methylimino-4-imidazolidinone, and the Z-product is separated
from the resulting E-Z mixture; or
b) (Z)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-
imidazolidinone is reacted with a methylating agent.
`~ - 3 -
: , , . ;
`'',.
1~963~S ~-
The imidazolidinone starting material utilized in
embodiment (a) of this process has the formula
~0
~N~N~ ¦
N--C H3
The E- and Z-isomers of the imidazolidinone starting
materials utilized in embodiment (b) of this process have the
formulae
~ ~N~l~ E 2
- H
~H3
lo and
CH3
NH
respectively.
- 4 -
~C~9638S
- - 5 -
The condensation of an indole-3-aldehyde derlvatlve with
compound II,in accordance with embodiment (a) of the present
process, can be carried out in a manner known per se, e.g. by
heating e~uimolar quantities of said starting materials in the
presence of acondensation agent, at a temperature up to the
reflux temperature of the reaction mixture, ~referably at a
temperature of from about 50 to about 150C. Examples of
condensation agents which can be utilized in the above reaction
are ali~hatic carboxvlic acids and the alkali metal salts of
these acids, e.g. acetic acid containing anhydrous sodium
acetate, secondary or tertiary amines, e.g. piperidine, or
mixtures thereof.
The methylation in accordance with embodiment (b) of the
present process can be carried out in a manner known per se,
for example by heating 5-(indol-3-ylmethylene)-1,3-dimethyl-2-
imino-4-imidazolidinone optionally substituted in position 6 by
lower alkyl,with a methylating a~ent, such as methyl iodide,
dimethyl sulfate or methylated derivatives-of dimethyl
sulphoxide, in an inert solvent, such as diethyl ether or
ethanol, at a temperature up to the reflux temperature of the
` reaction mixture.
5-(indol-3-ylmethvlene)-1,3-dimethvl-2-imino-4-
imidazolidinone is novel and forms also part of the invention.
It can be prepared by condensing indole-3-aldehyde with
;3~5
1,3-dimethyl-2-imino-4-imidazolidinone, in a manner analogous
to that described above for embodiment (a).
5-(Indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-
imidazolidinone has antidepressant activity. This can be
demonstrated in warm-blood animals using standard procedure.
: . . . - . .
For example, the antagonism of tetrabenazine induced
ptosis is demonstrated in male mice weighing 18-25 g. Groups
of 10 mice each are administered tetrabenazine methanesulpho-
nate at a dose of 100 mg/kg, one hour after oral administration
of the compounds to be tested. One hour after tetrabenazine
administration, each mouse is observed for the presence or
absence of ptosis. An ED50 value for the antagonism of tetra-
benazine induced ptosis is then determined. (E)-5-(Indol-3-
ylmethylene)--1,3-dimethyl-2-methylimino-4-imidazolidinone was
found to have an ED50 of 5 mg/kg.
1~963~5 7 _
5-(Indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-
imidazolidinone has antidepressant properties qualitatively
similar to those compounds such as imipramine, harmaline and
pargyline, which are known for their therapeutic uses and
properties. In contradistinction to these known compounds,
5-(indol-3-ylmethvlene)-1,3-dimethyl-2-methylimino-4-
imidazolidinone has no anticholinergic or cardiovascular
side effects. Furthermore, said known compounds are more
toxic than 5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-
4-imidazolidinone as can be seen from the following acute
toxicity data, expressed in LD50 mg/kg in mice:
.
(E)-5-(indol-3-
ylmethylene)-1,3-
dimethyl-2-
methylimino-4-
Compounds imidazolidinone imipraminepargyline harmaline
_
LD50 P-- 900 430 720 380
LD50 i-p- 670 125 390 120
5-(Indol-3-y~tethylene)-1,3-dimeth,1-2-methylimino-4-imidazolidin-
one is useful for the treatment of depressions. It can be used
in medicine in the form of pharmaceutical pre~arations which
contain it in association with a compatible pharmaceutical
carrier, namely an oryanic or inorganic inert carrier material
suitable for enteral, e.g. oral, or parenteral administration.
1~9~385
- B_
Examples of such carrier materials are water, gelatin, lactose,
starch, talc, magnesium stearate, gums, vegetable oils and
petroleum jelly. The pharmaceutical preparations can be made up
in a solid form, e.g. as tablets, capsules, dragees or sup-
positories, or in a liquid form, e.g. as solutions, emulsionsor suspensions. The pharmaceutical preparations may be
sterilised and/or may contain compatible adjuvants such as
preservatives, stabilising agents, flavouring agents, colouring
agents, emulsifying agents, salts for varying the osmotic
pressure or buffering agents.
- ~Convenient pharmaceutical dosage forms contain about
. . .
1 to 100 mg of 5-(indol-3-ylmethylene)-1,3-dimethyl-2-
methylimino-4-imidazolidinone. Convenient oral dosages are in the
range of about 0,1 mg/kg per day to about 10 mg/kg per day.
Convenient parenteral dosages are in the range of about
0,01 mg/kg per day to about 0,5 mg/kg per day. However, the
ranges mentioned can be extended upwards or downwards depending
upon individual requirements.
~9~3~35 g
Example 1
5 g of 1,3-dimethyl-2-methylimino-4-imidazolidinone and
5 g indole-3-aldehyde are refluxed in piperidine for 3 hours.
The reaction mixture is poured into 250 ml of water, stirred
for 30 minutes, filtered, washed with water and dried. There
are obtained 8,45 g of (E)-5-~ndol-3-vlmethylene)-1,3-dimethyl-
2-methylimino-4-imidazolldinone.
The product recrystallizes from methanol in form of
yellow needles, m.p. 226,5-228C.
H n-m-r- (CD3cooD) ~ 9,Ol(lH,S), 7,78(1H,m~, 7,58 (lH,m),
7,30(2H,m), 6,87(1H,S), 3,33(3H,S), 3,22(3H,S), 3,13(3H,S).
The following data are obtained bv low resolution mass
; spectrometry:
M+ 268 (61,9%), 253 (21,6%), 170 (23,7%), 169 (33,0~),
155 (base peak), 128 (25,3%), 101 (19,1%).
Example 2
a) The ~reparation of the startinq material
255 mg of 1,3-dimethyl-2-imino-4-imidazolidinone
hydriodide and 145 mg of indole-3-aldehyde are refluxed
in 5 ml piperidine for 4 hours. After cooling, the reaction
:
1~963~5
--10 --
mixture is poured into 50 ml water. After stirring for 30
minutes the formed precipitate is filtered, washed with water
and dried. There are obtained 205 mg of (E)-5-tindol-3-yl-
methylene)-1,3-dimethyl-2-imino-4-imidazolidinone.
The product recrystallizes from methanol as fine,
yellow needles, m.p. 231,8-233,1C.
b) The ~rocess
500 mg of(E~indol-3-ylmethylene)-1,3-dimethyl-2-imino-
4-imidazolidinone are refluxed in methanol for 24 hours with
425 mg of methyl iodide. The product is chromatographed on
silica gel and alumina. There are obtained 107 mg of(E~5-
(indol-3-ylmethylene)-1,3-dimethvl-2-methylimino-4-imidazol-
idinone.
Example 3
A mixture of 5.10 g of indole-3-carboxaldehyde, 5.64 g
of dimethylcreatinine and 60 ml of pipe~dine was heated at
reflux for 3 hrs, cooled to room temperature and poured into
350 ml of water. The precipitate was collected by filtration
- and dried to give 8.2 g of yellow solid, m.~. 241-241.5,which
consisted of a 9:1 mixture of E- and Z-isomers. By heating a
solution of the crude product in 2 1 of methanol and 100 ml
of piperidine at reflux for 2 hrs and removal of the solvents,
a 1:1 mixture of E- and Z-isomers was obtained.
1~963~3S
11 -
A one-gram sam~le of the above mix~ure (1:1 ratio of
isomers) was digested wi~h 20 ml of hot acetone and the soluble
portion (565 mq) was applied directly to a column of 15 g of
silica gel prepared in ethyl acetate. Elution was carried out
with acetone collecting 20 ml fractions. Fractions 6, 7, and 8
were combined (144 mg) and crystallized from acetonitrile to
afford 126 mg of (Z)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-
methylimino -4-imidazolidinone as a pale yellow solid, m.p.
241-242. The analytical sample was recrystallized from
acetonitrile, m.p. 241-242 . Mass spectrum m/e 268; W (95
ethanol): 229nm ( 22,400), 271 nm (9200); 365 nm (22,450);
NMR (100 mHz, DMS0-d6): ~7.67 (s, lH, H-2), 6.75 (s,0.94 H,
CH=C-C0, major*), 6.48 (s, 0.06 H, C~-CC0, minor*).
Corresponding data for the E-isomer, which was isolated
by crystallization of 9:1 mixture of isomers from methanol/
methylene chloride: W (95% ethanol): 232nm ( 20,600), 276nm
(6950) 394nm (22,600); NMR (100 mHz, DMS0-d6): ~ 8.72 (broad,
lH, H-2); 6.47 (s, 0.67 H, CH=C-C0, major*), 6.30 (s, 0.33 H,
CH=C-C0, minor*).
.
* Attributed to the isomers of the C=N-CH3.
1~i963~5
,
- 12 -
Example A
Tablets of the following composition are manufactured in
conventional manner:
(E)-S-(indol-3-ylmethylene)-1,3-dimethYl-
2-methylimino-4-imidazolidinone S0 mg
Lactose 95 mg
Maize starch 100 mg
Talc 4,5 mg
Magnesium stearate 0,5 mg
1 Total weight 250,0 mg
.
,
